1. Field of Invention
The current invention relates to a method for the production of micron or nanometer size particles by precipitation, wherein a dispersion containing the substance of interest is contacted with a supercritical fluid antisolvent under near or supercritical conditions in order to maximize micro or nanoparticle formation. The invention also provides techniques to control the particle size, particle size distribution and particle morphology. The invention also includes supercritical fluid coating or composite material particle formation, wherein encapsulation of one substance by another substance or coprecipitation of more than one substance in the form of micro or nanoparticles are achieved in the supercritical fluid antisolvent.
2. Background and Prior Art
Nanoparticles are of considerable importance in numerous technological applications. Nanoparticles of materials in fact exhibit properties significantly different from those of the same material with larger sizes. Some nanostructured materials with novel properties include: fullerenes, zeolites, organic crystals, non-linear optical material, high temperature superconductors, molecular magnetic materials, starburst dendrimers, piezoelectric materials, shape changing alloys and pharmaceuticals. The novel properties of these nanostructured materials can be exploited and numerous potential applications can be developed by using them in different industries. One such industry where the need for nanoparticles is particularly pronounced is the pharmaceutical industry where nanoparticles of different pharmaceutical materials are used for designing xe2x80x98drug delivery systemsxe2x80x99 for controlled release and targeting.
Several techniques have been used in the past for the manufacture of nanoparticles but these techniques suffer from some inherent limitations. Some of the conventional techniques include: Spray drying, which is one of the well-known techniques for particle formation and can be used to produce particles of 5 xcexcm or less in size. The major disadvantage of this technique is that it requires high temperature in order to evaporate the solvent in use, and this makes it unsuitable for treating biological and pharmaceutical substances. Furthermore, the final product yield may be low in case of small-scale applications. Milling can be used to produce particles in the 10-50 xcexcm range, but the particles produced by this method have a broad size distribution. Fluid energy grinding can produce particles in the 1-10 xcexcm range but this process involves the use of high-velocity compressed air, which leads to electrostatically charged powders. In addition, particle size reduction by this process tends to be more efficient for hard and brittle materials such as salt and minerals, but much less so for soft powders, such as pharmaceuticals and other biological substances. Lyophilization produces particles in the desired range, but with a broad distribution. A main disadvantage of this process is that it employs the use of organic solvents that may be unsuitable for pharmaceutical substances. In addition, control of particle size can also be difficult, and a secondary drying step is required to remove residual solvents. In the case of precipitation of protein particles, not all proteins can be lyophilized to stable products, and the process must be tailored to each protein.
Thus, none of these methods are entirely satisfactory, and it is therefore important to explore alternative methods that will produce particles from 5 xcexcm down to as low as 10 nm.
Particle Technology Based on Supercritical Fluids
One of the first uses of supercritical fluids in particle formation was proposed by Krukonis et al. in 1984 for processing a wide variety of difficult-to-handle solids. Since then, several experimental studies have been conducted to develop methods for particle formation using this technology. The two primary methods utilizing supercritical fluid technology for particle processing include Supercritical Antisolvent (SAS) Precipitation technique and the Rapid Expansion of Supercritical Solutions (RESS) technique. For many years now, these techniques have been successfully used to produce microparticles of various compounds including difficult to handle explosives (Gallagher et al., 1989), lysozyme, trypsin (Winter et al, 1993), insulin (Yeo et al., 1993; Winter et al, 1993), prednisolone acetate (U.S. Pat. No. 5,803,966), polystyrene (Dixon et al., 1993), HYAFF-11 polymers (Benedetti et al., 1997), different steroids (Larson and King, 1985), and numerous other organic substances. Other areas of application of supercritical fluids include formation of solvent free, drug loaded polymer micro-spheres for controlled drug release of therapeutic agents (Tom et al., 1992; Mueller and Fischer, 1989), production of ultra-fine and chemically pure ceramic precursors (Matson et al., 1985 a,b, 1987 a,b; Peterson et al. 1985), formation of intimate mixtures of ceramic precursors (Matson et al., 1987a), and for formulation of crystalline powders of labile pharmaceutical drugs. Dixon and coworkers (1993) used the supercritical CO2 antisolvent process to make polystyrene particles ranging from 0.1 to 20 xcexcm by spraying polymer/toluene solutions into CO2 of varying densities. A major advantage of supercritical fluid precipitation process is that they can generate particles having a narrow size distribution unlike other conventional processes that provide a wide size distribution. Further the particles formed by supercritical fluid precipitation process are free of organic solvents and the formation of powdered blends, thin films and micro-encapsulation of materials is straightforward.
The Working of the RESS Technique
In the RESS process, the solid of interest is first solubilized in supercritical CO2 and then sprayed through a nozzle into a low-pressure gaseous medium. Rapid expansion of the solution on being passed through the nozzle causes a reduction in CO2 density and also a reduction in the solvent power of supercritical CO2 and this subsequently leads to the recrystallization of the solid in the form of fine particles.
RESS provides a useful tool for controlling the size and morphology of the precipitated powders. The influence of operating conditions on the process has been studied by several investigators, sometimes with different and conflicting results (Larson and King, 1985; Mohamed et al., 1989; Peterson et al., 1985). When RESS is carried out in the usual mode, solvent free particles are obtained which makes the technique advantageous for processing pharmaceutical substances. No surfactants or nucleating media are required to trigger the nucleation and the solvent is removed by a simple mechanical separation.
One of the main constraints in the development of the RESS process however is supercritical fluid solvent capacity. For example, carbon dioxide, which is the preferred solvent in many applications, has a low solubility towards polar substances. Different supercritical fluids can be chosen in case of such a problem: a second solvent (cosolvent) can be added to enhance the CO2 solvent capacity, but these solvents remains within the precipitated product as impurities. In general, polymers possess low solubility in supercritical fluids, including CO2 (with or without cosolvents), and for such materials other processing methods are more suitable.
The Working of the SAS Process
In the SAS process, the supercritical fluid is used as the antisolvent. First the solid of interest is dissolved in a suitable organic solvent. Then this solution is introduced into the supercritical fluid using a nozzle. The supercritical fluid dissolves the solvent, precipitating the solid out as fine particles.
The volumetric expansion of the liquid when in contact with the SCF plays a key role in the process. For example, experiments conducted by Yeo et al. (1993a,b) for dimethylsulfoxide (DMSO)-CO2 system at two temperatures, shows that CO2 produces a remarkably high volumetric expansion of DMSO (as high as 1000%) near the mixture""s critical point. The increase of antisolvent amount in the mixed solvent and the evaporation of the organic liquid into the SCF eventually cause the precipitation of the solute as fine particles.
Several methods of applying the SAS technique have also been proposed. In the semibatch mode, the SCF is introduced continuously at the operating pressure into a stationary bulk liquid phase (Gallagher et al., 1989; Krukonis, 1988). If the liquid solution and the SCF are fed continuously to the precipitation tank, a SAS continuous process takes place (Yeo et al., 1993a,b). When the solvent used has a high volatility, it is possible to continuously feed the solution and the supercritical fluid into the precipitation vessel and, at the same time to discharge the dry precipitated particles (Randolph et al., 1993). Finally, a full batch mode is performed where the solution is loaded with the supercritical solvent from the initial condition at P=1 atm. to the high pressure (Yeo et al., 1993a,b).
Note that, in all cases, a cleaning step is necessary after the precipitation step in order to completely remove the liquid solvent from the particles. One of the interesting features of SAS is that the particles may be dried with CO2, and the CO2 may be depressurized at supercritical fluid conditions. Supercritical fluid drying removes the solvent thoroughly, which is often a major challenge. When liquids are evaporated from a matrix, the surface tension of the shrinking droplets often causes the matrix to collapse due to capillary forces. For a supercritical fluid, there is no surface tension, and the surface forces due to adsorption are minimal, so that the structure is preserved. Indeed the world""s lightest solids have been formed with critical point drying (Rangarajan and Lira, 1991).
Current Limitations of the SAS Process
The SAS technique can be used to produce particles having a narrow size distribution in the 1-10 xcexcm size range. Unfortunately these techniques cannot produce much smaller particles in the nanometer range. Nanometer size particles are extremely important for many pharmaceutical applications. New applications of nanoparticles of other substances can also emerge if the nanoparticles are manufactured successfully. In any SAS technology, mass transfer rate of the antisolvent into the droplet is the key factor in obtaining a high super-saturation rate and a smaller particle size, and hence mass transfer is the limiting factor in the SAS process. Techniques that can enhance mass transfer and provide faster diffusion of CO2 into the droplets are thus needed for the formation of smaller particles having a narrower size distribution. Operating temperature, pressure, concentration of the injecting solution, and flow rate of the solution have so far been investigated as size control parameters but none of these parameters were found to have a significant effect on the particle size over a wide range.
In the past few years several modifications (mostly in the manner of jet break up) in the SAS process have been proposed in order to overcome some of its limitations. For example in PCT publication WO 95/01221 the use of a coaxial nozzle for co-introduction of supercritical fluid and the solution has been proposed. Such nozzles cause effective breakup or atomization of the solution jet into tiny droplets. But, again a rigorous size control process variable is lacking. The use of high frequency sound waves for atomization has been known for many years for the atomization of liquid surfaces into tiny droplets. High frequency sound waves can be generated using various types of transducers namely piezoelectric, magnetorestrictive, electromagnetic, and pneumatic devices.
A specialized ultrasonic nozzle (Sonotek, 120 khz) was employed by Randolph et al. (1993) in the precipitation of poly (L-lactic acid) particles using the SAS technique. But they were unsuccessful in reducing the particle size as a result of the use of ultrasound. U.S. Pat. Nos. 5,833,891 and 5,874,029 disclose the use of ultrasound in small particle production. They disclose the use of a commercial ultrasonic nozzle (Sonomist, Model 600-1) for the droplet atomization. The sonic waves in this case are created when an energizing gas passes through a resonator cavity at the velocity of sound. The frequency of the sonic waves created is not constant and it is difficult to specify the frequency of the sound waves generated. Trying to vary the sonic energy might interfere with other process conditions and as a result it may not be used as a size control variable.
The Supercritical Antisolvent Precipitation with Enhanced Mass Transfer (SAS-EM) Process
The present invention provides a novel way to produce very small particles in the nanometer range, having a narrow size distribution. It also provides techniques to control the particle size. The processes and methods involved in the invention can be used for producing nanoparticles of a wide variety of materials such as polymers, chemicals, pesticides, explosives, coatings, catalysts and pharmaceuticals. Like the SAS technique, the current invention also uses a supercritical fluid as the antisolvent, but in this invention the dispersion jet is deflected by a vibrating surface that atomizes the jet into micro-droplets. The dispersion jet once introduced into supercritical fluid and onto the vibrating surface spreads evenly over the surface forming a thin liquid film. A set of wavelets then form on the free liquid layer due to the vibrating surface. The oscillatory vibrations of the liquid surface causes these wavelets to increase in amplitude until the wavelet tips break off and the droplets are emitted from the surface into the supercritical fluid media. Rapid transfer of CO2 into these droplets and the solvent out of these droplets causes them to expand rapidly, leading to a decrease in the droplet""s ability to keep the solute molecules dissolved causing the molecules to precipitate as fine particles. The vibration field generated by the vibrating surface inside the supercritical phase helps in enhancing mass transfer between the solvent and the supercritical fluid due to increased turbulence and mixing. The reduced mean droplet diameter coupled with enhanced turbulence within the supercritical phase cause rapid precipitation of the particles and thus act as major factors that are responsible for the formation of nanoparticles.
The present invention uses high frequency vibrations for atomization. The atomization process is brought about by introducing the dispersion on to a surface vibrating at a high frequency. No specialized nozzles are necessary in this invention. Any tube made of a standard material (for example: Stainless Steel, Fused Silica) can be used to spray the dispersion onto the horn surface. The diameter of the tube can be varied based on the desired size and desired yield of the micronized particles.
A schematic representation of the apparatus used for particles processing using the SAS-EM technique in the batch mode has been shown in FIG. 1. All the particle precipitation runs can be carried out using the methods in the invention either in the batch mode or in the semibatch mode. The first step, as in any antisolvent precipitation technique involving supercritical fluids, is filling up the particle production vessel with the antisolvent. This is done up to the desired operating pressure which is typically around or above the critical pressure of the antisolvent. Any antisolvent can be used including carbon dioxide, propane, butane, isobutene, nitrous oxide, sulfur hexafluoride and trifluoromethane, but carbon dioxide is the most preferred antisolvent due to its low cost, environmental friendliness and the ease of availability. The temperature inside the vessel is maintained constant at the desired value by placing the vessel in a temperature controlled zone. The temperature is typically above or around the critical temperature of the antisolvent. Dispersion containing desired substance is prepared. The horn inside the vessel is then turned on to vibrate at the desired amplitude by adjusting the input power to the vibrating source. The horn in fact provides the vibrating surface inside the supercritical phase for both dispersion jet atomization and increased mixing. The dispersion is then injected inside the precipitation chamber through a silica capillary tube, onto the vibrating surface. It is important to note here that tubes having different diameters can be used to carry out the precipitation process but in our case a 75 xcexcm (internal diameter) capillary tube was used. As the dispersion jet makes contact with the vibrating horn surface, it is atomized into tiny droplets and particles are formed due to the rapid removal of the solvent by supercritical CO2 from these droplets. Motion between the particles inside the chamber is increased due to the vibration field generated by the vibration surface, which in turn prevents them from agglomerating together and also increases the mass transfer rate of CO2 into the droplet, and the solvent out of the droplet.
In one preferred embodiment of the current invention the precipitation or recrystallization process using SAS-EM is carried out in a continuous manner. In this form of the invention the supercritical fluid is preheated and pumped into the vessel in a continuous manner at a desired flow rate. A preheated dispersion, having at least one solid of interest dissolved in at least one suitable solvent, is then injected into the vessel and onto the vibrating surface inside the precipitation vessel in a continuous manner at a desired flow rate. CO2 flow rate is kept high enough to completely dry the particles and remove all solvents.
A major advantage of the present invention over other forms of supercritical fluid particle precipitation techniques is that the sizes of the particles formed by this technique can be easily controlled by changing the vibration intensity of the deflecting surface, which in turn can be controlled by adjusting the input power to the vibrating source. For instance the size control parameters investigated so far in the SAS process are pressure and temperature of the antisolvent, concentration of the dispersion and the flow rate of the dispersion into the supercritical fluid antisolvent. All these parameters are not robust enough to generate a pronounced change in particle size. Besides, conflicting results have been obtained by different researchers about the actual effect of these parameters on particle size and distribution and no general trend has been established.
Another major advantage of the present invention is that it can be used to produce nanoparticles of compounds that cannot be obtained using the SAS method. In other words compounds that give long fibers or large crystals using the SAS technique can be processed using the SAS-EM technique to form nanoparticles or microparticles.
One of the main requirements of such small particles in several applications is a narrow particle size distribution. SAS-EM can be used to produce particles with narrow size distributions as a result of uniform droplet atomization.
In another preferred embodiment of the current invention encapsulation of one substance can be achieved using another substance to form coated nanoparticles. The core particle to be coated is dispersed in a suitable medium and mixed with a dispersion containing the desired substance and sprayed on to the deflecting surface in the vessel to obtain very small particles coated with the desired substance. Change in vibration intensity is used to decrease the particle size of such coated or encapsulated particles. Composite nanoparticles of two or more substances can also be obtained using the preferred embodiments of the current invention. In this aspect of the invention, the dispersion for injection is prepared by dissolving the substances to be co-precipitated in a suitable solvent or a mixture of solvents. Surfactants may also be employed for dispersing some substances in the suitable medium or solvent. The above dispersion is then sprayed onto the deflecting vibrating surface for atomization and production of particles. For example the co precipitation can be used to produce drug loaded polymer nanoparticles or magnetite encapsulated polymer nanoparticles that can be used for controlled release and drug targeting.